Cytokines represent a large number of secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, and in regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Conversely, mutations that affect cytokines and cytokine signal pathways underlie a variety of primary immunodeficiencies. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). After activation of receptor-associated Jaks, the next step in signal transduction is the activation of latent, cytosolic transcription factors that can also bind activated cytokine receptors. These factors are called STATs (signal transducers and activators of transcription). The function of STAT proteins in immune cells has been a focus of this lab for two decades. Work by NIH scientists has revealed that mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in nonhematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Consequently, the potential efficacy of HSCT for HIES is difficult to predict. To begin to dissect the importance of STAT3 in hematopoietic and nonhematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild-type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES. Many cytokines that activate STAT3 can also activate STAT1. This year we examined the relative contributions of STAT1 and STAT3 in signaling by two related cytokines, IL-6 and IL-27 and employed using genetic models of cells lacking STAT1 or STAT3 and chromatin immunoprecipitation-sequencing (ChIP-seq) to better understand the function of these transcription factors. Pertinent to this project, we used T cells from patients at the NIH Clinical Cener with gain-of-function STAT1 mutations. These patients are susceptible to fungal infections and have impaired Th17 differentiation, like HIES patients. We found that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. However, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action.
| Gadina, Massimo; Johnson, Catrina; Schwartz, Daniella et al. (2018) Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J Leukoc Biol 104:499-514 |
| Schwartz, Daniella M; Kanno, Yuka; Villarino, Alejandro et al. (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17:78 |
| Villarino, Alejandro V; Kanno, Yuka; O'Shea, John J (2017) Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 18:374-384 |
| Afzali, Behdad; Grönholm, Juha; Vandrovcova, Jana et al. (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18:813-823 |
| O'Shea, John J; Schwartz, Daniella M; Villarino, Alejandro V et al. (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311-28 |
| Villarino, Alejandro V; Kanno, Yuka; Ferdinand, John R et al. (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21-7 |
| Hirahara, Kiyoshi; Onodera, Atsushi; Villarino, Alejandro V et al. (2015) Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity. Immunity 42:877-89 |
| Steward-Tharp, Scott M; Laurence, Arian; Kanno, Yuka et al. (2014) A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123:2978-87 |
| O'Shea, John J; Holland, Steven M; Staudt, Louis M (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368:161-70 |
| Kontzias, Apostolos; Kotlyar, Alexander; Laurence, Arian et al. (2012) Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 12:464-70 |
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